Coronary heart disease leading to acute coronary syndromes (ACS) is the leading cause of mortality in the United States, and chest pain accounts for more than 8 million emergency room visits annually. However, acute myocardial infarction (AMI) is often misdiagnosed in emergency rooms, and many patients with AMI are discharged from emergency rooms without recognition.
Electrophysiology of the Heart
Transmembrane ionic currents are ultimately responsible for the cardiac potentials that are recorded as an ECG. The ECG is the final outcome of a complex series of physiological and technological processes. Transmembrane ionic currents are generated by ion fluxes across cell membranes and between adjacent cells. These currents are synthesized by cardiac activation and recovery sequences to generate a cardiac electrical field in and around the heart that varies with time during the cardiac cycle. This electrical field passes through numerous other structures, including the lungs, blood and skeletal muscle, that perturb the cardiac electrical field as it passes through them. Braunwald's Heart Disease, 8th Ed., Saunders, Elsevier (2008), Chapter 12, at p. 149. The currents reaching the skin are then detected by electrodes placed in specific locations on the extremities and torso that are configured to produce leads. The outputs of these leads are amplified, filtered, and displayed by various electronic devices to produce an electrocardiographic recording, and diagnostic criteria are applied to these recordings to produce an interpretation.
The Cardiac Dipole
Two point sources of equal strength but of opposite polarity located very near each other, such as a current source and a current sink, can be represented as a current dipole. Thus, activation of a single cardiac fiber can be modeled as a current dipole that moves in the direction of propagation of activation. Such a dipole is fully characterized by three parameters: strength or dipole moment, location and orientation. Dipole moment is proportional to the rate of change of intracellular potential. Likewise, multiple adjacent cardiac fibers are activated in synchrony to produce an activation front, which creates a dipole oriented in the direction of activation. The net effect of all the dipoles in this wave front is a single dipole with a strength and orientation equal to the (vector) sum of all the simultaneously active component dipoles. Id. at 150
A current dipole produces a characteristic potential field with positive potentials projected ahead of it and negative potentials projected behind it. The actual potential recorded at any site within this field is directly proportional to the dipole moment, inversely proportional to the square of the distance from the dipole to the recording site, and directly proportional to the cosine of the angle between the axis of the dipole and a line drawn from the dipole to the recording site. Id. at 150
This relationship between activation direction, orientation of the current dipole, and polarity of potentials describes the fundamental relationship between the polarity of potentials sensed by an electrode and the direction of movement of an activation front, i.e., an electrode senses positive potentials when an activation front is moving toward it and negative potentials when the activation front is moving away from it. Id at 150
Transmission factors are contents of the three-dimensional physical environment (called the volume conductor), which modifies the cardiac electrical field in significant ways. Transmission factors may be grouped into four broad categories.
Cellular factors determine the intensity of current fluxes that result from local transmembrane potential gradients; they include intracellular and extracellular resistances and the concentrations of relevant ions, e.g., the sodium ion. Lower ion concentrations reduce the intensity of current flow and reduce extracellular potentials.
Cardiac factors affect the relationship of one cardiac cell to another. Two major factors are (1) anisotropy, the property of cardiac tissue that results in greater current flow and more rapid propagation along the length of a fiber than across its width; and (2) the presence of connective tissue between cardiac fibers, which disrupts effective electrical coupling of adjacent fibers.
Extracardiac factors encompass all the tissues and structures that lie between the activation region and the body surface, including the ventricular walls, intracardiac and intrathoracic blood, pericardium, lungs, skeletal muscle, subcutaneous fat, and skin. These tissues alter the cardiac field because of differences in the electrical resistivity of adjacent tissues, i.e., the presence of electrical inhomogeneities within the torso.
Other factors include changes in the distance between the heart and the recording electrode, which reduce potential magnitudes in proportion to the square of the distance and the eccentricity of the heart within the chest (meaning it lies closer to the anterior than to the posterior region of the torso, and the right ventricle and anteroseptal aspect of the left ventricle are located closer to the anterior chest wall than other parts of the left ventricle and the atria, which means that electrocardiographic potentials will be higher anteriorly than posteriorly, and waveforms projected from the anterior left ventricle to the chest wall will be greater than those generated by posterior ventricular regions. Id. at 151
The Cardiac Cycle
The heart is a current generator, and its electrical field is well known to be overwhelmingly dipolar.
The term “cardiac cycle” is used to refer to all or any of the electrical and mechanical events related to the coronary blood flow or blood pressure that occur from the beginning of one heartbeat to the beginning of the next. Blood pressure increases and decreases throughout the cardiac cycle. The frequency of the cardiac cycle is the heart rate. Every single ‘beat’ of the heart involves five major stages: (1) “late diastole,” which is when the semilunar valves close, the atrioventricular (AV) valves open and the whole heart is relaxed; (2) “atrial systole,” which is when the myocardium of the left and right atria are contracting, AV valves open and blood flows from atrium to ventricle; (3) “isovolumic ventricular contraction,” which is when the ventricles begin to contract, AV and semilunar valves close, and there is no change in volume; (4) “ventricular ejection,” which is when the ventricles are emptied but still contracting and the semilunar valves are open; and (5) “isovolumic ventricular relaxation,” when pressure decreases, no blood is entering the ventricles, the ventricles stop contracting and begin to relax, and the semilunar valves are shut because blood in the aorta is pushing them shut. The cardiac cycle is coordinated by a series of electrical impulses that are produced by specialized heart cells found within the sino-atrial node and the atrioventricular node. The heart is activated and recovers during each cardiac cycle in a characteristic manner determined by the anatomy and physiology of working cardiac muscle and the specialized cardiac conduction systems. P. Libby et al., Eds., Braunwald's Heart Disease, 8th Ed., Elsevier, Inc., Philadelphia (2008) at 155.
The normal cardiac cycle begins with spontaneous depolarization of the sinus node, an area of specialized tissue situated in the high right atrium (RA). A wave of electrical depolarization then spreads through the RA and across the inter-atrial septum into the left atrium (LA). Id.
The atria are separated from the ventricles by an electrically inert fibrous ring, so that in the normal heart the only route of transmission of electrical depolarization from atria to ventricles is through the atrioventricular (AV) node. Id. The AV node delays the electrical signal for a short time, and then the wave of depolarization spreads down the interventricular septum (IVS), via the bundle of His and the right and left bundle branches, into the right (RV) and left (LV) ventricles. With normal conduction the two ventricles contract simultaneously. Id.
After complete depolarization of the heart, the myocardium must then repolarize, before it can be ready to depolarize again for the next cardiac cycle.
The Standard 12-lead Electrocardiogram
A standard surface ECG is recorded showing 12 different lead ‘directions’ from eight independent leads, though only 10 recording electrodes on the skin are required to achieve this. Six of these electrodes are placed on the chest overlying the heart to record the six chest or precordial leads. Four electrodes are placed on the limbs to record the six limb leads. In a standard ECG, it is essential that each of the 10 recording electrodes is placed in its correct position, otherwise the appearance of the ECG will be changed significantly, preventing correct interpretation.
For simple bipolar leads, such as leads I, II and III, the lead vectors are directed from the negative electrode toward the positive one. For the augmented limb and precordial leads, the origin of the lead vector lies at the midpoint of the axis connecting the electrodes that make up the compound electrode, i.e., for lead aVL, the vector points from the midpoint of the axis connecting the right arm and left leg electrodes toward the left arm. For the precordial leads, the lead vector points from the center of the triangle formed by the three standard limb leads to the precordial electrode site.
The limb leads record the ECG in the coronal plane, and so can be used to determine the electrical axis (which is usually measured only in the coronal plane). The limb leads are called leads I, II, Ill, aVR, aVL and aVF. A horizontal line through the heart and directed to the left (exactly in the direction of lead I) is conventionally labelled as the reference point of 0 degrees (0°). The directions from which other leads ‘look’ at the heart are described in terms of the angle in degrees from this baseline.
The chest leads record the ECG in the transverse or horizontal plane, and are called V1, V2, V3, V4, V5 and V6. Other lead conventions exist and may be used clinically including V7, V8, and V9, which are recorded from the posterior left thorax, and V3R, V4R, V5R, and V6R, which are recorded from the anterior right thorax.
Improved ECG Using a Universal Transformation Matrix
An improved ECG technology to detect myocardial injury uses the mathematical techniques of abstract factor analysis and the simplex optimization algorithm to derive a universal transformation matrix that is applicable to all patients and is independent of time (U.S. Pat. No. 6,901,285, incorporated by reference). This universal transformation matrix is applicable when needed and does not require the acquisition of a complete n-lead ECG for each patient prior to its implementation. In order to do this, one first measures and digitizes the voltage-time data for some set of ECG leads to define an ECG training set. Once the voltage-time data arrays have been acquired, an abstract factor analysis (“AFA”) technique is applied to each ECG voltage-time data array in a training set in order to minimize the error in the measured arrays. The final step is then to apply a simplex optimization technique (“SOP”) to the training set in order to derive a universal transformation matrix applicable to all patients, and is time independent. This universal transformation matrix can then be applied to a standard measured 3 lead subsystem (the measured I, aVF and V2 leads) to derive the standard 12 lead ECG as well as other systems, and can generate at least 22 leads to enable a more accurate interpretation of cardiac electrical activity. These derived ECG leads account for approximately 99% of the information content when compared to observed lead measurements.
The ECG is the first test in the initial evaluation of chest pain patients, but multiple studies have demonstrated that the ECG has low sensitivity in initially diagnosing AMI.
Cardiac serum markers are an important supplement to the ECG in the assessment and risk stratification in acute myocardial ischemic injury. Serum troponin evaluation has recently become the gold standard for the diagnosis of myocardial necrosis. However, serum troponin results are generally not immediately available, nor are they obtained continuously in real time, and initial treatment protocols typically must be implemented by relying only on the initial patient evaluation and the associated 12-lead ECG interpretation.
Rapid diagnosis of acute myocardial ischemic injury, including AMI, is the key to implementing immediate treatment. For presumed acute coronary syndrome (ACS) patients, the ECG and cardiac serum markers are typically acquired at the time of patient arrival and every several hours thereafter, for up to 24 hours of patient observation to identify the developments of an ACS. The patient may be at risk during the time between these serum markers and ECG acquisitions, especially if the patient has silent ischemic injuries. Furthermore, approximately 95% of patients who visit emergency rooms with chest pains are sent home without treatment. These patients may also be at risk.